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Kavisha S. Jayasundara, Edward C. Keystone and Jayson L. Parker DOI: 10.3899/jrheum.120005 http://www.jrheum.org/content/early/2012/08/29/jrheum.120005 1. Sign up for our monthly e-table of contents http://www.jrheum.org/cgi/alerts/etoc 2. Information on Subscriptions http://jrheum.com/subscribe.html 3. Have us contact your library about access options Refer_your_library@jrheum.com 4. Information on permissions/orders of reprints http://jrheum.com/reprints.html
The Journal of Rheumatology is a monthly international serial edited by Duncan A. Gordon featuring research articles on clinical subjects from scientists working in rheumatology and related fields.
parker@utoronto. The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease. Ontario. The exclusion criteria for drugs in this study: drugs that were started in phase I studies prior to January 1998 for this indication..5%−1% of the general US population1. Bristol-Myers Squibb. Without adequate early treatment. Genzyme. Although MTX shows reduced morbidity measures. but biologics seemed to exhibit a higher success rate overall. Nycomed. Hoffmann-LaRoche Inc. We conducted a systematic review to determine the risk of drug failure in clinical testing with patients with moderate to severe rheumatoid arthritis (RA). F. Dr. He has held consulting agreements and advisory board memberships with Abbott Laboratories. Merck. respiratory disease. Master of Biotechnology Program. Pfizer Pharmaceuticals. M. infections. Abbott. Amgen Inc. University of Toronto. F.5. Leslie Dan Faculty of Pharmacy. AstraZeneca Pharma. J. Amgen. longterm conventional DMARD therapy is only effective in a proportion of patients8. Department of Biology. Biotech. RA will cause permanent joint damage as well as serious functional disability leading to reduced quality of life3. and he has held Speaker Honoraria agreements with Abbott Laboratories. The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease. Therapies for RA were investigated by reviewing phase I to phase III studies conducted from December 1998 to March 2011. All rights reserved. Merck. JAYASUNDARA. Clinical studies equally comprised investigations of small molecules and biological agents. Canada. Pfizer Pharmaceuticals. Pfizer Pharmaceuticals. Ontario L5L 1C6.L. Centocor Inc. including tumor necrosis factor (TNF)-blocking agents. From 1998 to 2009. Biotest. the number of therapeutic alternatives for RA has increased. The American College of Rheumatology Subcommittee Rheumatoid Arthritis recommends that patients with suspected RA confirm the diagnosis and initiate therapy with disease-modifying antirheumatic drugs (DMARD) within 3 months of presenting symptoms6. Merck. PhD. A search in clinicaltrials. KEYSTONE. the frequency of clinical failures exceeded commercial failures. The remainder of patients are therefore still at risk for disease progression and require additional treatment. Toronto. and JAYSON L.ca Accepted for publication July 10. Novartis Pharmaceuticals. Jayasundara. University of Toronto. or studies that enrolled patients who were methotrexate-naive and/or had failed biologic therapy. Methods.gov and approved drugs for the indication yielded a total of 69 drugs that met the study criteria. University of Toronto Mississauga. E-mail: jayson. and UCB. Director. Hoffmann-La Roche Inc. Results. T cell costimulatory receptor-blocking protein. FRCPC. 3359 Mississauga Road North. Conclusion. RA holds an impressive record during a time when the overall productiv- Personal non-commercial use only.3899/jrheum. Address correspondence to Dr. RA prevalence rates increase progressively with age. Trial failures were classified as either commercial or clinical failures. with a peak onset in the fifth decade and a higher incidence rate in women than in men2. UCB. K. and the Department of Biology. Clinical trial success rates were calculated and compared to industry standards. The Journal of Rheumatology Copyright © 2012. AstraZeneca Pharmaceuticals LP. doi:10.. et al: Clinical trial risk in RA 1 . Parker. E. and antibody against IL-6 receptor9. He has worked in the pharmaceutical industry with infliximab. MD.. Mount Sinai Hospital.C. The cumulative success rate was determined to be 16%. with 10 new drug approvals. Jayasundara.S. Bristol-Myers Squibb Company. Genentech Inc. Clinical trial risk in RA with the 84% failure rate reported here is at par with industry performance and phase II success rate seems to be highly predictive of phase III success.L.. and UCB. 2012. Objective. Centocor Inc. University of Toronto. Low-dose methotrexate (MTX) is the main choice among physicians. PARKER ABSTRACT. EDWARD C. University of Toronto. With the rather high number of approvals. Dr. Hoffmann-La Roche Inc. J. Although it may affect people of all ages. Keystone.. and some malignancies4. Almost all are biologic agents developed against specific targets that play a role in RA pathogenesis. and Janssen Inc. Bristol-Myers Squibb Company. Canada. SB-2071. From the Leslie Dan Faculty of Pharmacy. Mississauga..Review Risk of Failure of a Clinical Drug Trial in Patients with Moderate to Severe Rheumatoid Arthritis KAVISHA S. For each phase. Parker consults for investment firms that may or may not have investments owning products in this study. which is equivalent to the industry standard of 16%. Keystone has received funding for research from Abbott Laboratories.. The severe form of RA is associated with premature mortality due to cardiovascular disease. Parker. interleukin 1β (IL-1β)-blocking recombinant soluble receptor. Mount Sinai Hospital. (J Rheumatol First Release Sept 1 2012. B cell-depleting monoclonal antibody. F.120005) Key Indexing Terms: RHEUMATOID ARTHRITIS BIOLOGICS CLINICAL TRIAL RISK SUCCESS RATE DISEASE-MODIFYING ANTIRHEUMATIC DRUG Rheumatoid arthritis (RA) is a chronic and systemic inflammatory autoimmune disease affecting 0.
Phase I/II trials were considered as phase I. or microorganism — are complex in structure and thus are usually not fully characterized”10. Cumulative rates refer to the probability of completing the current clinical trial and any preceding clinical trial phase successfully (i. The clinical trial success rate was calculated by Classification of clinical trial failure. Simponi (golimumab). the phase I success rate was calculated to be 88%. and 6 drugs had successfully completed phase III. The following search terms were used: “rheumatoid arthritis + clinical trial. the success rate for RA was 16%. Approved drugs with phase I trials conducted before 1998 were omitted from our study. Drugs were separated into clinical and commercial failures based on the reasons for the halt of the drug’s progress. Examination of clinical trials success rates in this disease area would help to determine how to mitigate clinical trial risk for investigational drugs that are currently being evaluated. to our knowledge. A clinical failure was defined as one where a drug failed to meet its primary endpoint in phase II or phase III. on the other hand. comprising over 85 drug candidates and multiple hits per drug. all trials were industry-sponsored and had US sites. For example. Drug programs that completed a trial in the last 2 years without any indication of clinical failure were considered “unclassified/unknown” and were not included in the analysis. or had significant safety issues during any of the phases. The Website clinicaltrials. The Journal of Rheumatology Copyright © 2012.” “rheumatoid arthritis + press release. Cimzia (certolizumab pegol). 66% for industry. The phase II success rate was 22%. Phase III clinical testing was classified as a “success” if the US Food and Drug Administration (FDA) approved the compound and it remained on the market as of March 2011. A list of 69 drug candidates was found to meet the specified criteria of this study. Cumulatively. The latter were extracted from previously reported studies for industry as a whole. or III clinical studies in second-line therapy of moderate to severe RA from January 1998 to March 2011 were included in the analysis.” Firms were considered biotechnology companies if they were listed in the NASDAQ biotechnology index at the time of phase I start of the drug program. much higher than the industry standard of 64%.gov was the main source of data for our study. Drug candidates were also classified as biologics or small molecules to elucidate trends between drug properties and clinical success. Phase III yielded a success rate of 86% for this indication. RESULTS An initial search for drug candidates in RA on clinicaltrials. which is at par with the industry standard of 16%. Databases and online tools. the product of probabilities). Press releases served as a supplementary tool in compiling a list of eligible drug programs. and Actemra (tocilizumab). MATERIALS AND METHODS Study eligibility. it was considered a clinical failure. Competing drug programs.e. Phase I.” “rheumatoid arthritis + press news. Drugs were classified as small molecules or biologics. Orencia (abatacept).120005 . All rights reserved. and testing was done from January 1998 to March 2011.gov yielded over 1200 hits. 39:11. The approved drug candidates that fit within our study criteria were Humira (adalimumab).ity of the pharmaceutical industry. Drug and company classifications. Fifty-nine drugs had successfully completed phase I between 1998 and March 2011. Success rate for each phase was calculated and compared to industry standards. as follows: Success rate for phase x = (number of drug candidates that successfully completed phase x)/ (total number of drugs that completed phase x) The “number of drug candidates that successfully completed phase x” refers to the number of drug candidates that successfully completed phase x and moved on to phase x + 1 (and/or phase x + 2). Phase I ownership of each drug entity was categorized as “biotech” or “pharmaceutical. was defined as a drug program that showed no indications of clinical failure in press releases or conference proceedings yet no further clinical testing of the drug was conducted in 2 or more years. Phase I and I/II clinical testing was classified as a “success” if the drug advanced to phase II.. Drugs that were administered as monotherapy as well as concomitant therapy were eligible. encompassing many therapeutic areas11. Moreover. doi:10. which is significantly lower than the industry standard of 39%.” Clinical trial success rate. To determine the risk of clinical trial failure in RA therapy. a drug that is currently in phase III is a success for both phase I and phase II given that those trials were completed in the specified time period of this study.” and “rheumatoid arthritis + trial results. drug candidates intended to treat patients with moderate to severe RA were reviewed.3899/jrheum. successful drugs were compared against failed drugs for each phase of clinical testing. As shown in Figure 1. Selected drug candidates had clinical study sites in the United States. which aligns with the lower success rate (transitional probability) depicted in Figure 1 (14 were due to clinical reasons and 8 were due to commercial reasons). while phase II/III trials were considered as phase II. 2 The Journal of Rheumatology 2012. Biologics were defined in accord with the FDA guidance stating that “biological products are generally derived from living material — human. Commercial failure. The denominator includes the number of drugs that completed phase x but did not move on to phase x + 1. Clinical trial outcome classification. lack of financing. This is the first study of its type. 3 were commercial and 2 were clinical. A drug was considered a “line extension” if it had been previously approved for a different indication and subsequently entered testing in RA. to quantify the clinical trial risk in this disease area. Phase II clinical testing was classified as a “success” if the drug advanced to phase III. Rituxin (rituximab). Phase II had the highest number of failures overall. The nature of failure (clinical vs commercial) was examined for each phase along with the type of therapy used (monotherapy vs concomitant therapy). Companies that were not listed on the index and had a market capitalization over $1 billion US were classified as pharmaceutical companies. has declined9. 10 drugs had successfully completed phase II. Clinical trial failure was separated into clinical and commercial failure. animal. Patients who were MTX-naive and patients who had failed biological treatment were also excluded. For phase I failures. If a clinical trial was “withdrawn” or a drug was withdrawn from the market. Only 1 failure was Personal non-commercial use only. Companies that did not meet the above criteria were not classified. determining the percentage of successful trials out of the total number of trials in a particular phase. In this systematic review. and revisions of revenue forecast for the drug candidate could all result in commercial failures. II. as measured by the number of new drugs being introduced to market.
Figure 3. in phase II. Drugs that used both regimens were double-counted. Drugs that entered phase I clinical testing during or after 1998 were tracked until March 2011. therefore. Previously reported success rates (calculated using the same methodologies as in this analysis) for other disease areas include 11% for non- Figure 2. Clinical trial success rates in rheumatoid arthritis based on drug regimen (monotherapy vs concomitant therapy). There were no significant differences in success rates for all 3 phases when comparing the 2 treatment regimens. et al: Clinical trial risk in RA 3 . Industry pass rates are extracted from previously published studies. observed for phase III and it was clinical (owing to ocrelizumab). the success rate for monotherapy was 27% in comparison to 24% seen for concomitant therapy. Jayasundara. Drug sponsorship was classified into pharmaceutical and biotechnology companies based on phase I ownership. the clinical trial success rate for moderate to severe RA was found to be 16%. there were more clinical failures than commercial failures (17 clinical vs 11 commercial). only one will make it to market successfully. This means that out of 6 drug candidates clinically investigated in this disease area. and the commercial failures seemed to be more concentrated early in clinical testing (phase I and II). Clinical trial success rates in rheumatoid arthritis based on drug property (biologic or small molecule). Personal non-commercial use only. biologics had a success rate of 41%. Drug sponsorship. monotherapy showed a success rate of 88% versus 89% for concomitant. Both types of companies showed very similar transitional probabilities for all clinical study phases. a greater number of drugs were investigated as concomitant therapy in comparison to monotherapy. For phase II. For phase I. which is equivalent to the industry standard. The Journal of Rheumatology Copyright © 2012. Properties of drug candidates are examined in Figure 3. All rights reserved. Overall. does not seem to influence the success rate for therapies of moderate to severe RA. “Success rate” refers to the likelihood that a drug would complete the current phase and advance to the next phase of clinical testing (or approval if currently in phase III) based on the collected dataset. Clinical trial success rates in moderate to severe rheumatoid arthritis (RA). and all approved drug candidates included in this analysis were biologic agents. A 100% success rate was seen for monotherapy in phase III and 86% for concomitant therapy. The numbers of successful drug candidates were also distributed very similarly across the 2 types of industry sponsors. Figure 2 illustrates the success rate of each phase classified by monotherapy and concomitant therapy. while small molecules had a mere 5%. DISCUSSION In our study. This illustrates the success of biologics in comparison to small molecules in this indication. However.Figure 1. a cumulative success rate of 31% was seen for biologics. Overall. Phase I showed an equivalent success rate for small molecules and for biologics at 88%. Drugs that used both concomitant and monotherapy regimens were included in both groups. and no small molecules were investigated in this phase. Overall. as depicted in Figure 4. and their respective transitional probabilities were calculated. The cumulative transitional probability was 18% for pharmaceutical drugs and 20% for biotechnology drugs. A 100% success rate was seen for biologics in phase III.
120005 . and other DMARD. Nevertheless. In such a scenario. leflunomide. Generally. Clinical trial success rate in rheumatoid arthritis based on whether the drug’s phase I ownership belonged to pharma or biotech company. Concomitant therapy seems to be more prevalent in RA in comparison to monotherapy. The benefits of monotherapy include simpler study design and lack of drug-drug interactions as well as reduced combined side effects. Such results were not seen in indications such as Crohn’s disease and non-Hodgkin’s lymphoma12. combination treatments with DMARD have shown greater clinical utility as well as cessation of disease progression in RA15. This may lead to an even higher number of clinical failures than determined here.3899/jrheum. developing small molecule therapies with adequate efficacy and safety has proved to be extremely difficult9. Haraoui B. The Journal of Rheumatology Copyright © 2012. Currently. This explains the high overall frequency of concomitant treatment in comparison to monotherapy. Rheum Dis Clin North Am 2001. the high rate of clinical failure in phase II could be due to poor animal models that do not translate well into clinical testing. their clinical significance remains to be evaluated9. with some studies including hydroxychloroquine. when success rates were calculated for both treatment regimens. Gabriel SE.16. Epidemiology of adult rheumatoid arthritis. The data sources used in our study and the unsophisticated methods for identifying commercial failures may pose a limitation to this analysis. It is possible that clinical failures were not reported in the resources used for this analysis and therefore they were actually identified as commercial failures.7% for human immunodeficiency virus14. It is possible that the high success rate of phase III could extend to small molecules. Bykerk VP. are currently being evaluated in late clinical testing9. Drosos AA. doi:10. however. novel disease-targeting and thorough understanding of disease pathogenesis is required to overcome the 84% failure rate in drug development. Hodgkin’s lymphoma12. Baron M.14:11-3. when administered alongside the novel agent. no significant differences were seen for each phase. but because of the safety concerns associated with them (e. 4 The Journal of Rheumatology 2012. increases the return on investment for the companies that are involved in clinical development. phase Ib studies are conducted by companies to determine efficacy of molecules at an earlier stage in testing. 3.4:130-6. Our review of the reported clinical trials for RA suggests that even with many established drugs on the market. Autoimmun Rev 2005. et al. Khraishi M.13. 2. It is imperative to eliminate unsuccessful drug candidates early in clinical testing so that resources can be allocated to drug candidates with more potential. success rates in RA clinical studies are not higher than industry standards. Boire G. Our systematic review shows that there is a higher predictive value associated with phase II that may lead to a high phase III success rate in RA. hypertension and altered liver function). Canadian consensus statement on early optimal therapy in early rheumatoid arthritis. The highest number of failures was seen in phase II. In addition. The trend of a lower phase II success rate followed by a higher phase III success rate is the ideal scenario for drug development. suggesting that in RA. with significantly more clinical failures in comparison to commercial failures. It is also possible that several studies have been terminated but not publicly.Figure 4. janus-associated kinase and spleen tyrosine kinase inhibitors. 19% for Crohn’s disease13. Personal non-commercial use only. This. Biologics encompassed the majority of investigational drug candidates in our study and exhibited a higher success rate in comparison to small molecules. and 16. Concomitant therapy may appear to be the more attractive option because of the lack of combined immunosuppression offered by DMARD. Alamanos Y. and it is phase II transitional probability that seems to dictate the cumulative success rate. CRAJ 2004.27:269-81. Phase II results appeared to be highly predictive of phase III outcome. The epidemiology of rheumatoid arthritis. This could be because drugs that use monotherapy and concomitant treatment were double-counted in the analysis and therefore allowed a higher success rate for monotherapy (which has a lower prevalence overall). 39:11.g. REFERENCES 1. all approved drugs included in our study were also biologics. Despite the risk of toxicity and adverse effects. All rights reserved. Even with a high number of drug approvals in the last decade.. The majority of combination therapies included MTX. given that these trials are concerned with pharmacokinetic and pharmacodynamic properties of the drug entity and overall safety of the compound. sulfasalazine. 2 small-molecule drug classes. It has been predicted by many in the pharmaceutical industry that biological DMARD therapy would soon be replaced by oral small molecules. in turn. intermediate data can be a reliable tool in forecasting future study success. such as MTX. a high success rate is expected for phase I. These studies may decrease overall success rates in phase I. However. LeClercq S.
Arthritis Rheum 2008. Drug development risk in HIV-1 clinical trials: The effect of drug class. Parker JL. [Internet. Dikranian AH. US Food and Drug Administration. The Journal of Rheumatology Copyright © 2012. 14. Zhang ZY. Wilson A.358:903-11. J Pharm Pharmaceut Sci 2011. Scott DL. 2012. 15. Morales-Torres JL. Lancet 2002. What is a biological product? [Internet.] Available from: http://www. The success rate of new drug development in clinical trials: Crohn’s disease. Treatment of rheumatoid arthritis with Syk kinase inhibitor: A twelve-week. Methotrexate and mortality in patients with rheumatoid arthritis: A prospective study. Arthritis Rheum 2002. 6. Fogler WE. Jayasundara.46:328-46.gov/AboutFDA/Transparency/Basics/ucm194516. 12. Kavanaugh A.359:1173-7. Review: Rheumatoid arthritis.ddw-online. 8. Personal non-commercial use only. Medrano-Ramirez G. All rights reserved.376:1094-108. Polmar SH. Wolfe F. Arthritis Rheum 2010. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Hernan MA. Buckstein R. Clin Pharmacol Ther 2010. Kohler JC.4. Weinblatt M. et al.10:1-2.fda. placebo-controlled trial. 5. 7. Osborne BJ. Seeger JD. Robins JM.htm 11. Dixon W. Drug Discovery World 2008. 10. J Pharmaceut Health Serv Res 2011. Guidelines for the management of rheumatoid arthritis: 2002 update. Lancet 2010. J Pharm Pharmaceut Sci 2010. Lancet 2001. Trends in risks associated with new drug development: Success rates for investigational drugs. DiMasi JA. Parker JL. No evidence of association between anti-tumour necrosis factor treatment and mortality in patients with rheumatoid arthritis.13:227-35. Kaul R. Rheumatol Clin 2009. et al: Clinical trial risk in RA 5 . Watson K. randomized. New drugs for rheumatoid arthritis: The industry point of view [editorial].html 16.] Available from: http://www. Accessed July 26.com/s/ therapeutics/ p92869/treating-rheumatoid-arthritis-with-dmardsand-biologicsfall-2008. Weinblatt ME. 13. Rheumatoid arthritis. Choi HK. Feldman L. Lee D. 2012.2:211–6.3:272-7.13:191-7.58:3309-18. Treating rheumatoid arthritis with DMARDs and biologics. Huizinga TW. Parker JL. Wolfe F. Burgos-Vargas R. Lunt M. Accessed July 26. 9.62:3145-53. Clinical trial risk in non-Hodgkin’s lymphoma: Endpoint and target selection.
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